Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Scripps Research scientists establish new class of anti-diabetic compound

05.09.2011
Research offers hope for better treatments for diabetes patients

In a joint study, scientists from The Scripps Research Institute and Harvard University's Dana-Farber Cancer Institute have established a new class of anti-diabetic compound that targets a unique molecular switch.

The finding paves the way for the development of anti-diabetic therapeutics with minimal adverse side effects plaguing currently available drugs such as Avandia (rosiglitazone), scheduled to be removed from pharmacy shelves this fall due to concerns about increased risk of heart attack.

The new study, led by Patrick R. Griffin, professor and chair of the Department of Molecular Therapeutics at Scripps Florida, Bruce Spiegelman, professor of cell biology at the Dana-Farber Cancer Institute, and Theodore Kamenecka, associate scientific director of medicinal chemistry at Scripps Florida, was published September 4, 2011, in the journal Nature. The study describes a new compound known as SR1664.

"In this study, we demonstrate that we have discovered novel compounds that work effectively through a unique mechanism of action on a well-validated clinical target for diabetes," said Griffin. "This unique mechanism of action appears to significantly limit side effects associated with marketed drugs. This study is a great example of interdisciplinary, inter-institutional collaboration with chemistry, biochemistry, structural biology, and pharmacology."

"It appears that we may have an opportunity to develop entire new classes of drugs for diabetes and perhaps other metabolic disorders," said Spiegelman.

Diabetes affects nearly 24 million children and adults in the United States, according to the America Diabetes Association.

A Viable Therapeutic Target

The study follows previous research by the authors published last year in Nature (Volume 466, Issue 7305, 451-456) that suggested an obesity-linked mechanism that may be involved in the development of insulin-resistance. In that research, the team found disruptions in various genes when a protein known as PPARγ undergoes phosphorylation (when a phosphate group is added to a protein) by the kinase Cdk5, an enzyme involved in a number of important sensory pathways.

The new study confirms that blockage of Cdk5's action on PPARG is a viable therapeutic approach for development of anti-diabetic agents. The new SR1664 compound is a potent binder to the nuclear receptor PPARG, but does not activate gene transcription via the receptor's normal mechanism.

While Griffin stressed the difficulty of fully assessing side effects of new compounds such as SR1664, the new research is extremely positive in that it clearly demonstrated fewer of the major well-documented side effects, such as weight gain or increased plasma volume, from SR1664 as compared to Avandia in diabetic mice.

While both the mice treated with Avandia and those treated with SR1664 demonstrated improved blood sugar levels, those treated with Avandia showed weight gain and increased fluid retention within a few days of beginning treatment; those being treated with SR1664 showed none of these side effects. In cell culture studies, SR1664 also appeared to have little effect on bone formation, nor did it increase fat generation in bone cells, another side effect of current therapies such as Avandia.

While S1664 likely will not be developed as a drug, it now serves as a molecular scaffolding for the creation of similar compounds with potential to treat diabetes. "With data in hand showing that our compounds are as efficacious as the currently marketed PPARG modulators, while demonstrating a significant improvement of side effects in limited studies, we are now advancing newer compounds with improved pharmaceutical properties into additional studies," Griffin said.

The first authors, denoted as equal contributors to this study, "Anti-Diabetic Actions of a Non-Agonist PPARG Ligand Blocking Cdk5-Mediated Phosphorylation," are Jang Hyun Choi and Alexander S. Banks of Dana-Farber Cancer Institute and Theodore M. Kamenecka and Scott A. Busby of The Scripps Research Institute. Other authors include Michael J. Chalmers, Naresh Kumar, Dana S. Kuruvilla, Youseung Shin, Yuanjun He, David Marciano, and Michael D. Cameron of Scripps Research; Dina Laznik of the Dana-Farber Cancer Institute; Michael J. Jurczak and Gerald I. Shulman of the Howard Hughes Medical Institute; Stephan C. Schürer and Dušica Vidović of the University of Miami; and John B. Bruning of Texas A&M University.

The study was supported by The National Institutes of Health.

Mika Ono | EurekAlert!
Further information:
http://www.scripps.edu

Further reports about: Cancer Dana-Farber Nature Immunology Scripps metabolic disorder weight gain

More articles from Health and Medicine:

nachricht Nanoparticles as a Solution against Antibiotic Resistance?
15.12.2017 | Friedrich-Schiller-Universität Jena

nachricht Plasmonic biosensors enable development of new easy-to-use health tests
14.12.2017 | Aalto University

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: First-of-its-kind chemical oscillator offers new level of molecular control

DNA molecules that follow specific instructions could offer more precise molecular control of synthetic chemical systems, a discovery that opens the door for engineers to create molecular machines with new and complex behaviors.

Researchers have created chemical amplifiers and a chemical oscillator using a systematic method that has the potential to embed sophisticated circuit...

Im Focus: Long-lived storage of a photonic qubit for worldwide teleportation

MPQ scientists achieve long storage times for photonic quantum bits which break the lower bound for direct teleportation in a global quantum network.

Concerning the development of quantum memories for the realization of global quantum networks, scientists of the Quantum Dynamics Division led by Professor...

Im Focus: Electromagnetic water cloak eliminates drag and wake

Detailed calculations show water cloaks are feasible with today's technology

Researchers have developed a water cloaking concept based on electromagnetic forces that could eliminate an object's wake, greatly reducing its drag while...

Im Focus: Scientists channel graphene to understand filtration and ion transport into cells

Tiny pores at a cell's entryway act as miniature bouncers, letting in some electrically charged atoms--ions--but blocking others. Operating as exquisitely sensitive filters, these "ion channels" play a critical role in biological functions such as muscle contraction and the firing of brain cells.

To rapidly transport the right ions through the cell membrane, the tiny channels rely on a complex interplay between the ions and surrounding molecules,...

Im Focus: Towards data storage at the single molecule level

The miniaturization of the current technology of storage media is hindered by fundamental limits of quantum mechanics. A new approach consists in using so-called spin-crossover molecules as the smallest possible storage unit. Similar to normal hard drives, these special molecules can save information via their magnetic state. A research team from Kiel University has now managed to successfully place a new class of spin-crossover molecules onto a surface and to improve the molecule’s storage capacity. The storage density of conventional hard drives could therefore theoretically be increased by more than one hundred fold. The study has been published in the scientific journal Nano Letters.

Over the past few years, the building blocks of storage media have gotten ever smaller. But further miniaturization of the current technology is hindered by...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

AKL’18: The opportunities and challenges of digitalization in the laser industry

07.12.2017 | Event News

 
Latest News

Engineers program tiny robots to move, think like insects

15.12.2017 | Power and Electrical Engineering

One in 5 materials chemistry papers may be wrong, study suggests

15.12.2017 | Materials Sciences

New antbird species discovered in Peru by LSU ornithologists

15.12.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>